We are examining how rodent microglia respond to methamphetamine in both a chronic and acute exposure model. Ongoing work has identified dosing of methamphetamine that causes unique activation of microglia in the striatum that can be used to examine how activated microglia can affect the surround neurons. We have recently developed a novel microglial cell line that has a modified HIV provirus inserted into the genome. This provirus lacks the gag and pol genes but expresses a luciferase which can be used to monitor effectors of proviral transcriptional activity. We have used CRISPR to target the long terminal repeat (LTR) promoter of HIV in this cell line and are using it to evaluate CRISPR-based approaches to alter HIV proviral activity in microglia. Microglia are notoriously difficult to target with transgenic material. We are working on a non-viral approach to delivery transgenic material (DNA, RNA, CRISPR ribonucleoproteins) to microglia. Finally, using a modified form of the transgenic construct described above for the cell line, we are developing a transgenic rat model of HIV pathogenesis in microglia and astrocytes.